Human immunodeficiency virus (HIV) infection is a major health problem worldwide. Recently, highly active antiretroviral therapy (HAART), including HIV-1 protease inhibitors (PI), has dramatically improved longevity of HIV-infected patients. However, such therapy causes development of 'HAART-induced lipodystrophy' characterized by marked loss of subcutaneous fat from the face, arms, legs and hips, accumulation of fat around the neck and trunk, and increased prevalence of insulin resistance, diabetes and dyslipidemia. Management of lipodystrophy and its metabolic lifestyle changes as well as novel therapies for its management. The project therefore has the following aims: 1) to compare acceptability and metabolic effects of diets rich in carbohydrates and cis-monounsaturated fats, 2) to compare effects of a supervised aerobic exercise regimen and dietary advice to dietary advice alone on metabolic variables and body fat distribution, 3) to compare lipid-lowering effects of n-3 polyunsaturated fats alone and in combination with sitostanol and 4) to study efficacy and safety of recombinant methionyl leptin (r-metHuleptin) in improving insulin sensitivity, dyslipidemia and body fat distribution in patients with HAART-induced lipodystrophy and metabolic complications. To accomplish these aims, we will enroll 130 patients with HAART-induced lipodystrophy or metabolic complications in randomized, crossover studies (aims 1 and 3) and randomized, parallel design studies (aims 2 and 4). We will study body fat distribution by anthropometry + dual energy X-ray absorptiometry and magnetic resonance imaging and will measure insulin sensitivity (aims 2 and 4) and plasma lipoproteins, glucose tolerance and other metabolic variables (all aims). Our results may help in designing therapeutic approaches to HAART-induced lipodystrophy and its metabolic complications. Additionally, the study may help prevent these problems in HIV-infected patients being initiated on PI-containing HAART.